OPRM1, OPRK1, and COMT genetic polymorphisms associated with opioid effects on experimental pain: a randomized, double-blind, placebo-controlled study

Ho, Kin‐Yip; Wallace, Margaret R.; Staud, Roland; Fillingim, Roger B.

doi:10.1038/s41397-019-0131-z

Cited by 21 publications

(19 citation statements)

References 40 publications

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“…Studies in animals and humans have shown that the OPRM1 polymorphism 118A > G leads to interindividual differences in the sensitivity to pain and analgesic response to opioids and that carriers of the 118G allele may require higher opioid doses compared with carriers of the 118A allele ( Stamer et al, 2016 ). As it was recently shown in a randomized placebo-controlled trial including 108 healthy individuals, the AA genotype of rs4680 or A_T_C_A/A_T_C_A ( rs6269_rs4633_ rs4818_rs4680 ) diplotype of COMT gene, combined with the AG genotype of OPRM1 A118G , showed significantly increased pressure pain threshold from butorphanol ( Mura et al, 2013 ; Ho et al, 2020 ). However, studies investigating these SNPs specifically in migraine patients are missing.…”

Section: Pharmacogenetics Of Important Drugs Used In Migraine Tension...mentioning

confidence: 81%

Pharmacogenetics in Primary Headache Disorders

et al. 2022

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Primary headache disorders, such as migraine, tension-type headache (TTH), and cluster headache, belong to the most common neurological disorders affecting a high percentage of people worldwide. Headache induces a high burden for the affected individuals on the personal level, with a strong impact on life quality, daily life management, and causes immense costs for the healthcare systems. Although a relatively broad spectrum of different pharmacological classes for the treatment of headache disorders are available, treatment effectiveness is often limited by high variances in therapy responses. Genetic variants can influence the individual treatment success by influencing pharmacokinetics or pharmacodynamics of the therapeutic as investigated in the research field of pharmacogenetics. This review summarizes the current knowledge on important primary headache disorders, including migraine, TTH, and cluster headache. We also summarize current acute and preventive treatment options for the three headache disorders based on drug classes and compounds taking important therapy guidelines into consideration. Importantly, the work summarizes and discusses the role of genetic polymorphisms regarding their impact on metabolism safety and the effect of therapeutics that are used to treat migraine, cluster headache, and TTH exploring drug classes such as nonsteroidal anti-inflammatory drugs, triptans, antidepressants, anticonvulsants, calcium channel blockers, drugs with effect on the renin–angiotensin system, and novel headache therapeutics such as ditans, anti-calcitonin-gene-related peptide antibodies, and gepants. Genetic variants in important phase I-, II-, and III-associated genes such as cytochrome P450 genes, UGT genes, and different transporter genes are scrutinized as well as variants in genes important for pharmacodynamics and several functions outside the pharmacokinetic and pharmacodynamic spectrum. Finally, the article evaluates the potential and limitations of pharmacogenetic approaches for individual therapy adjustments in headache disorders.

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Section: Pharmacogenetics Of Important Drugs Used In Migraine Tension...mentioning

confidence: 81%

Pharmacogenetics in Primary Headache Disorders

et al. 2022

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“…One of the proteins that shows the highest frequency of replication is opioid receptor kappa (OPRK1). The polymorphism of this protein has recently been reported to affect pain relief from opioids [43] . Studies on cancer and postoperative patients show that carriers of the homozygote G allele have higher pain scores and require higher morphine doses, thereby indicating reduced signaling efficacy and a possibly declined receptor expression [44] .…”

Section: Resultsmentioning

confidence: 99%

“…The polymorphism of this protein has recently been reported to affect pain relief from opioids. [43] Studies on cancer and postoperative patients show that carriers of the homozygote G allele have higher pain scores and require higher morphine doses, thereby indicating reduced signaling efficacy and a possibly declined receptor expression. [44] A total of 52 drugs target this protein, and some of them show as ADR 'Drug abuse', 'Drug tolerance', 'Drug hypersensitivity', 'Drug ineffective', 'Drug intolerance', or 'Drug withdrawal syndrome' and so might be related to this SV.…”

Section: Wwwmolinfcommentioning

confidence: 99%

Drug‐target‐ADR Network and Possible Implications of Structural Variants in Adverse Events

Dafniet

Cerisier

Audouze

et al. 2020

Molecular Informatics

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Adverse drug reactions (ADRs) are of major concern in drug safety. However, due to the biological complexity of human systems, understanding the underlying mechanisms involved in development of ADRs remains a challenging task. Here, we applied network sciences to analyze a tripartite network between 1000 drugs, 1407 targets, and 6164 ADRs. It allowed us to suggest drug targets susceptible to be associated to ADRs and organs, based on the system organ class (SOC). Furthermore, a score was developed to determine the contribution of a set of proteins to ADRs. Finally, we identified proteins that might increase the susceptibility of genes to ADRs, on the basis of knowledge about genomic structural variation in genes encoding proteins targeted by drugs. Such analysis should pave the way to individualize drug therapy and precision medicine.

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“…Our research included the sequences of 31 pain-related genes, encompassing 18 pain perception genes: SCN9A , SCN10A , PRDM12 , ANO1 , CCK , MARK1 , MARK2 , RUNX1 , NGF , NTRK1 , CACNA1G , TRPV1 , TRPV4 , P2RX3 , P2RX4 , ASIC1 , ASIC3 and ASIC4 and 13 analgesia genes: CA8 , GRK2 , ARRB2 , KCNA1 , KCNA2 , TRAAK , KCNIP3 , KCNJ10 , ANO3 , OPRM1 , OPRD1 , OPRK1 , and OPRL1 . All the selected genes have been proven to be associated with the pain ( Supplementary Table S1 [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]). In total, 43 representatives of mammalian species were examined, including: 17 Cetacea, 4 Artiodactyla, 8 Carnivora, 2 Perissodactyla, 3 Chiroptera, 3 Primates, 1 Scandentia, 3 Rodentia, 1 Sirenia, and 1 Proboscidea.…”

Section: Methodsmentioning

confidence: 99%

Rubbing Salt in the Wound: Molecular Evolutionary Analysis of Pain-Related Genes Reveals the Pain Adaptation of Cetaceans in Seawater

Ding

et al. 2022

Animals

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Pain, usually caused by a strong or disruptive stimulus, is an unpleasant sensation that serves as a warning to organisms. To adapt to extreme environments, some terrestrial animals have evolved to be inherently insensitive to pain. Cetaceans are known as supposedly indifferent to pain from soft tissue injury representatives of marine mammals. However, the molecular mechanisms that explain how cetaceans are adapted to pain in response to seawater environment remain unclear. Here, we performed a molecular evolutionary analysis of pain-related genes in selected representatives of cetaceans. ASIC4 gene was identified to be pseudogenized in all odontocetes (toothed whales) except from Physeter macrocephalus (sperm whales), and relaxed selection of this gene was detected in toothed whales with pseudogenized ASIC4. In addition, positive selection was detected in pain perception (i.e., ASIC3, ANO1, CCK, and SCN9A) and analgesia (i.e., ASIC3, ANO1, CCK, and SCN9A) genes among the examined cetaceans. In this study, potential convergent amino acid substitutions within predicted proteins were found among the examined cetaceans and other terrestrial mammals, inhabiting extreme environments (e.g., V441I of TRPV1 in cetaceans and naked mole rats). Moreover, specific amino acid substitutions within predicted sequences of several proteins were found in the studied representatives of cetaceans (e.g., F56L and D163A of ASIC3, E88G of GRK2, and F159L of OPRD1). Most of the substitutions were located within important functional domains of proteins, affecting their protein functions. The above evidence suggests that cetaceans might have undergone adaptive molecular evolution in pain-related genes through different evolutionary patterns to adapt to pain, resulting in greater sensitivity to pain and more effective analgesia. This study could have implications for diagnosis and treatment of human pain.

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OPRM1, OPRK1, and COMT genetic polymorphisms associated with opioid effects on experimental pain: a randomized, double-blind, placebo-controlled study

Cited by 21 publications

References 40 publications

Pharmacogenetics in Primary Headache Disorders

Pharmacogenetics in Primary Headache Disorders

Drug‐target‐ADR Network and Possible Implications of Structural Variants in Adverse Events

Rubbing Salt in the Wound: Molecular Evolutionary Analysis of Pain-Related Genes Reveals the Pain Adaptation of Cetaceans in Seawater

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